Evaluation of the combination of nelarabine and fludarabine in leukemias: Clinical response, pharmacokinetics, and pharmacodynamics in leukemia cells

V. Gandhi, W. Plunkett, S. Weller, M. Du, M. Ayres, Jr Rodriguez C.O., P. Ramakrishna, G. L. Rosner, J. P. Hodge, S. O'Brien, M. J. Keating

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62 Scopus citations

Abstract

Purpose: A pilot protocol was designed to evaluate the efficacy of fludarabine with nelarabine (the pro-drug of arabinosylguanine [ara-G]) in patients with hematologic malignancies. The cellular pharmacokinetics was investigated to seek a relationship between response and accumulation of ara-G triphosphate (ara-GTP) in circulating leukemia cells and to evaluate biochemical modulation of cellular ara-GTP metabolism by fludarabine triphosphate. Patients and Methods: Nine of the 13 total patients had indolent leukemias, including six whose disease failed prior fludarabine therapy. Two patients had T-acute lymphoblastic leukemia, one had chronic myelogenous leukemia, and one had mycosis fungoides. Nelarabine (1.2 g/m2) was infused on days 1,3, and 5. On days 3 and 5, fludarabine (30 mg/m2) was administered 4 hours before the nelarabine infusion. Plasma and cellular pharmacokinetic measurements were conducted during the first 5 days. Results: Seven patients had a partial or complete response, six of whom had indolent leukemias. The disease in four responders had failed prior fludarabine therapy. The median peak intracellular concentrations of ara-GTP were significantly different (P = .001) in responders (890 μmol/L, n = 6) and nonresponders (30 μmol/L, n = 6). Also, there was a direct relationship between the peak fludarabine triphosphate and ara-GTP in each patient (r = 0.85). The cellular elimination of ara-GTP was slow (median, 35 hours; range, 18 to > 48 hours). The ratio of ara-GTP to its normal counterpart, deoxyguanosine triphosphate, was higher in each patient (median, 42; range, 14 to 1,092) than that of fludarabine triphosphate to its normal counterpart, deoxyadenosine triphosphate (median, 2.2; range, 0.2 to 27). Conclusion: Fludarabine plus nelarabine is an effective, well-tolerated regimen against leukemias. Clinical responses suggest the need for further exploration of nelarabine against fludarabine-refractory diseases. Determination of ara-GTP levels in the target tumor population may provide a prognostic test for the activity of nelarabine.

Original languageEnglish (US)
Pages (from-to)2142-2152
Number of pages11
JournalJournal of Clinical Oncology
Volume19
Issue number8
StatePublished - Apr 15 2001
Externally publishedYes

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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    Gandhi, V., Plunkett, W., Weller, S., Du, M., Ayres, M., Rodriguez C.O., J., Ramakrishna, P., Rosner, G. L., Hodge, J. P., O'Brien, S., & Keating, M. J. (2001). Evaluation of the combination of nelarabine and fludarabine in leukemias: Clinical response, pharmacokinetics, and pharmacodynamics in leukemia cells. Journal of Clinical Oncology, 19(8), 2142-2152.